PCI后抗血小板治疗(TCC).ppt

介入术后抗血小板治疗,一抗血小板药物作用机制和阿司匹林抵抗,不同的抗血小板药物作用机制,胶原 凝血酶 TXA2,阿司匹林,ADP,(纤维蛋白原受体）,氯吡格雷,TXA2,ADP,双嘧达莫,磷酸二酯酶,ADP,Gp IIb/IIIa,激活,COX,盐酸噻氯匹定,ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Schafer AI. Am J Med. 1996;101:199209.,Category % OR Acute MI Acute stroke Prior MI Prior stroke/TIA Other high risk Coronary artery disease (unstable angina, heart failure) Peripheral arterial disease (intermittent claudication) 22 2 % High risk of embolism (atrial fibrillation) Other (diabetes mellitus) All trials,1.0,0.5,0.0,1.5,2.0,Control Better,Antiplatelet Better,Antithrombotic Trialists Collaboration (ATC): Efficacy of Antiplatelet Therapy on Vascular Events*,* Vascular events = MI, stroke, or vascular death. OR, odds reduction; MI, myocardial infarction; TIA, tranient ischemic attack. Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86. (with permission),Aspirin Resistance: More Than Just a Laboratory Curiosity?,Bhatt DL. J Am CollCardiol.2004;43:1127-1129.,Genetic Polymorphisms COX-1 GP IIIa receptor Collagen receptor vWF receptor,Cellular Factors Insufficient suppression of COX-1 Overexpression of COX-2 mRNA Erythrocyte-induced platelet activation Increased norepinephrine Generation of 8-iso-PGF2,Clinical Factors Failure to prescribe Noncompliance Nonabsorption Interaction with ibuprofen Interaction with naproxen,Aspirin Resistance,Aspirin Resistance and the Risk of Cardiovacular Events in High Risk Patients,5529 pts from HOPE study with baseline urine samples,Case (n=488) Pts with CV events after randomization,Controls (n=488) Pts without CV events after randomization,Urinary 11-dehydro Thromboxane B2 (ng/mmol creatinine),15.1,15.1-21.8,21.9-33.8,33.8,1.0,1.3,1.4,1.8,MI, stroke or CV death (P=.01),Odd Ratio,Hypothesis: Incomplete inhibition of thromboxane B2 increases risk of cardiovascular event,Adapted from Eikelboom JW, et al. Circulation. 2002;105:1650-1655.,VerifyNowASA, ASA/clopidogrel (n=464), 26.9% ASA resistant,Aspirin-resistant,Aspirin-sensitive,n=125,P=0.007,n=339,CV Death MI CVA/TIA HospUA,Cumulative incidence of composite end point(%),Follow-up time (days),ASA Response and Long-Term CV Events,二、氯吡格雷的早期和长期应用 什么时间用？用多长时间？,CLARITY 急救亚组研究: 住院前氯吡格雷对比安慰剂(加溶栓治疗),ECG显示ST段恢复的患者 (%),在救护车上给予氯吡格雷的患者伴ST段恢复,Verheugt F et al. J Thromb Thrombolysis 2006;Dec 6 epub,p=0.02,p=0.05,给予负荷剂量后的时间,3,491名 76岁的 STEMI患者，接受溶栓治疗， 随机分组接受氯吡格雷或安慰剂，在救护车或入院时给药,STEMI, ST段抬高型心肌梗死; ECG, 心电图,47.2,37,63.2,52.7,90分钟,180分钟,试验,PCI后至30天的心血管死亡或心梗,Sabatine, et al. JAMA. 2005;294:1224-1232,PCI 预处理(300 mg负荷量) 事件,1.0,0.25,2.0,0.5,预处理更优,不预处理更优,OR (95% CI),PCI前3-24小时氯吡格雷 300mg预处理给予负荷剂量的时间越早，受益越大,UTVR: 紧急目标血管血运重建,Steinhubl S, et al. JAMA, 2002 288 2411 2420, JACC 2006; 47:939-943,氯吡格雷预处理对PCI显著有益,4,160名计划行 PCI的患者接受氯吡格雷 300 mg,PCI前氯吡格雷预处理的益处,引自: Szuk T et al. Am Heart J 2007;153:289295.,ARR, 绝地风险降低; TVR, 目标血管血运重建; PCI, 经皮冠脉介入术; CI, 可信区间; MI, 心肌梗死,ARR: 1.97 (95% CI, 0.813.13) p=0.02,重大不良事件发生的时间 (天),负荷量预处理,p=0.001,植入支架后给予负荷量,0.05,0.04,0.03,0.02,0.01,0.00,0,5,10,15,20,25,30,死亡、心梗或反复TVR的累积风险,早期使用氯吡格雷表现为使STR增多,血管造影前接受治疗的患者 (%),Spontaneous STR,p=0.045,p=94,p=0.33,p=0.96,p=0.70,206名因STEMI入院的连续患者，在 PCI前，18%的患者ST段自动恢复 (STR),Jabaren M et al. Am J Cardiol 2006;98:14351438,PCI术前早期使用氯吡格雷,PCI, 经皮冠脉介入术; STEMI, ST段抬高型心肌梗死,氯吡格雷可降低NSTEMI患者1年严重心脑血管不良事件发生率,1年事件率 (%),p0.001,*,*MACCE = 重大心脑血管不良事件 (死亡、非致命性再梗、脑卒中) Zeymer U et al: 私人沟通,20.8,8.5,2,28.1,9.4,5.8,1.9,15.6,0,5,10,15,20,25,30,死亡,再梗,脑卒中,MACCE,阿司匹林,阿司匹林 + 氯吡格雷,NSTEMI后给予氯吡格雷ACOS登记研究,ACOS Registry-Antiplatelet Therapy and 1-Year Mortality in ST-elevation MI,Mortality (%),ASA alone ASA + Clopidogrel,*P0.0001 vsASA alone.,Zeymeret al. EurHeart J.2006 October 16; Epubahead of print.,Steinhubl SR, Berger PB, Tift Mann III J, et al. JAMA, November 20, 2002-Vol 288, No 19: 2411-2420.,Clopidogrel,MI, Stroke or death(%),Months of Follow-up,0,3,6,9,12,8.5%,11.5%,0,5,10,15,CREDO:Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients,Placebo,荟萃分析表明： DES与BMS相比，迟发性血栓有升高的趋势,12个月后：5比0,12个月后：9比2,手术开始后的时间（月）,手术开始后的时间（月）,Stone et al, N Engl J Med 2007; 56:998-1008, Feb 13 2007, epub,Iakovou. JAMA 2005;293:2126,DES术后迟发性支架内血栓的独立危险因素 提前终止抗血小板治疗是主要原因之一,支架内血栓的死亡率为 45%,停用氯吡格雷后患者心源性死亡心梗的发生率明显升高 且大多数事件由血栓引起,BASKET-LATE 研究,Eisenstein, JAMA. 2007;297:(doi:10.1001/jama.297.2.joc60179),药物支架后应用氯吡格雷的长期临床效益,DES + 氯吡格雷12个月(n=252) : DES + 氯吡格雷12个月(n=276),0%,-3.5% P=0.004,3.5%,DES术后氯吡格雷治疗长期疗效 Duke Registry*,Endpoint (%),校正的死亡和心梗发生率（2年）,Eisenstein EL, et al. JAMA. 2007; 297(2):159-168,*DES=1501例, BMS=3165例,无论置入何种支架， 氯吡格雷应用越久，获益越多,J Am Coll Cardiol 2008;51:22207,未来双联抗血小板治疗更长的疗程？,Dual Antiplatelet Therapy Trial (DAPT): 30个月vs 12个月双重抗血小板在支架患者中的疗效 8个厂家出资10亿美元，入组2万例患者,FDA Townhall Meeting, TCT Oct 15, 2008,开放DAPT治疗,DAPT研究设计,双盲安慰剂随机对照(RCT): 12个月时明确符合入组条件12个月和30个月DAPT组的患者 联合主要终点：支架血栓和MACCE；次要终点：严重出血 33个月的随访包括3个月“反弹期” BMS组12个月vs30个月同期进行 研究参与者自行决定支架类型和噻氯匹啶药物的选择（氯吡格雷或普扎格雷）,DES n=15,245 BMS n=5,400,R DES n=12,196 BMS n=4,320,30 个月 DAPT 组,观察期,12个月 DAPT 组,观察期,初步阶段：入组,随机化：所有符合入组条件的患者,0 月,6个 月,12个 月,15个 月,30个 月,治疗结束,随访结束,33个 月,有MACCE*或严重出血的患者随访至12 个月，但是不符12个月时入组的入组条件,MACCE*: Major Adverse Cardiac and Cerebrovascular event 严重心脑血管不良反应,FDA Townhall Meeting, TCT Oct 15, 2008,三、氯吡格雷负荷量及相关问题 用什么样的剂量及三联抗血小板,Relation of Platelet Inhibition to Periprocedural Necrosis and MACE,DUAL RESISTANCE Study (N=150),% Patients with CK-MB Elevation,Myocardiol infarct Platelet Inhibition Major Adverse Cardiac Events,Lev et al. J Am Coll Cardiol.2006. Chen et al. J Am Coll Cardiol.2004.,ASA resistant,ASA sensitive,Clopidogrel resistant,Clopidogrel sensitive,Dual resistant,Dual sensitive,Relation of Platelet Inhibition to Periprocedural Necrosis and MACE,ASPIRIN Myonecrosis Study (n=151),% Patients with CK-MB and troponin I elevation,Magnitude of CK-MB elevation,Myocardiol infarct Platelet Inhibition Major Adverse Cardiac Events,P=0.006,P=0.012,Lev et al. J Am Coll Cardiol.2006. Chen et al. J Am Coll Cardiol.2004.,ISAR-CHOICE(300,600,900mg),von Beckerath et al. Circulation.2005.,ALBION: 氯吡格雷 600 Mg 可以更迅速地抑制血小板聚集,抑制血小板聚集 (%),更高剂量的负荷量伴更快速的抑制,103名非ST段抬高的ACS患者随机分配接受 300、600或900 mg 氯吡格雷,0,Montalescot et al. JACC 2006;48:931-8,0,50,10,20,30,40,1,2,3,4,5,6,时间(小时),5 mol/L ADP,*p0.05 与300 mg相比,900 mg,600 mg,300 mg,600 mg,300 mg,*,900 mg,*,ARMYDA-2 Trial,Primary Endpoint: death, MI, or TVR at 30 days,4%,0%,2%,4%,6%,8%,10%,12%,14%,High Dose,Standard Dose,12%,Clopidogrel Loading Dose 600 mg Pre-PCI,Clopidogrel Loading Dose 300 mg Pre-PCI,255 patients with stable CAD or NSTEMI prior to PCI 13% GP IIb/IIIa inhibitors 20% DES,Randomized 4-8 hrs Pre-PCI,p=0.041,Circulation 2005;111:2099-2106,600mg的氯吡格雷负荷剂量可降低后续事件的发生率,292名接受300或600 mg 氯吡格雷负荷剂量的支架植入的NSTE ACS连续患者,ST = 支架血栓形成 Cuisset et al. J Am Coll Cardiol 2006; 48:133945,无心血管事件生存 (%),100,80,90,95,p0.0024,300 mg,600 mg,事件 (%),心血管事件,0,12.5,2.5,7.5,10.0,脑卒中,300 mg,600 mg,30,20,10,0,85,时间(天),ACS 事件,ST,心血管 死亡,5.0,氯吡格雷 600 Mg与300 Mg负荷剂量,高负荷量氯吡格雷显著减少 急诊PCI后的紧急血运重建,30天时出现的死亡、心梗、 紧急血运重建或脑卒中 (%),600 mg负荷量可能比 300 mg负荷量更有效,165名行急诊PCI的STEMI患者,Jung et al. Am J Cardiol 2006; Oct 22-27 (TCT Abstracts),0,14,8,6,10,12,600 mg 负荷量,300 mg 负荷量,n=98,n=67,3%,11%,4,2,按紧急血运重建的差异驱动的主要终点,p=0.021,G. BIONDI-ZOCCAI, SCAI 2007,10项临床研究Meta分析： 600mg优于300mg,死亡/MI 30d,ISAR-REACT-2 Abciximab in non-STE ACS undergoing PCI pretreated with 600mg LD clopidogrel,JAMA 2006; 295 1531-38,8.9,11.9,%,1.4,1.4,%,Death, MI, or urgent TVR by 30 days RR 0.75 P=0.03,TIMI Major Bleed In-hospital P=NS,ISAR-REACT 2 Death, MI, or urgent TVR in Subsets With and Without Elevated Troponin Levels (0.03 g/L),0,5,10,15,20,25,30,Days After Randomization,Placebo Group (N=1010) Abciximab Group (N=1012),Troponin 0.03 g/L Log-Rank p = 0.02,Troponin 0.03 g/L Log-Rank p = 0.98,JAMA 2006; 295:1531-38,%,0,2,4,6,8,10,12,Follow-up duration (months),%,No. at risk,Log-Rank, P=0.0192,0,1,2,3,4,5,0.8%,0.1%,Triple group 965 957 953 Dual group 965 948 942,The DECREASE Registry Cumulative incidence of stent thrombosis,Dual antiplatelet therapy (n=965) Triple antiplatelet therapy (n=965),0,2,4,6,8,10,12,Follow-up duration (months),%,No. at risk,Log-Rank, P=0.0744,0,1,2,3,4,5,2.6%,1.4%,Triple group 965 955 950 Dual group 965 948 940,Cumulative incidence of Death or MI,Dual antiplatelet therapy (n=965) Triple antiplatelet therapy (n=965),研究设计,氯吡格雷高剂量组 氯吡格雷 600 mg负荷剂量第1天， 接第2-7天150 mg; 第8-30天75 mg,氯吡格雷标准剂量组 氯吡格雷 300 mg (+安慰剂) 第1天， 接第2-7天75 mg (+安慰剂); 第8-30天75 mg,随机分组,随机分组,ASA 低剂量组 第1天至少 300 mg; D2 - D30 75100 mg,ASA 高剂量组 第1天至少 300 mg; D2- D30 300 mg325 mg,ASA高剂量组 第1天至少 300 mg; D2- D30 300 mg325 mg,ASA低剂量组 第1天至少 300 mg; D2 - D30 75100 mg,计划早期介入治疗的 UA/NSTEMI患者， 即有意在24小时内尽早行PCI的患者,随机分组,PCI: 经皮冠脉介入术 UA/NSTEMI: 不稳定心绞痛/非ST段抬高型心梗,CURRENT,四、新型抗血小板药物的研究,JUMBO-TIMI 26 three doses of prasugrel vs clopidogrel in elective or urgent PCI (safety evaluation),Circulation 2005; 11:3366-73,1.7,1.2,%,7.2,9.4,%,Significant non-CABG Bleeding at 30days P=0.77,MACE at 30 days HR 0.76 P=0.26,PRINCIPLE TIMI 44 (Planned Elective PCI) PRIMARY EP Acute Phase: IPA 20 uM ADP,Prasugrel 60 mg,P0.0001 for each,IPA (%; 20 mM ADP),Hours,Circulation 2007;116:2923-32,Prasugrel 10 mg,Prasugrel 10 mg,Difference Between Treatments: 14.9 95% CI 10.6 19.3, P0.0001,IPA (%; 20 mM ADP),Days,Circulation 2007;116:2923-32,PRINCIPLE TIMI 44,PRIMARY EP Chronic Phase: IPA 20 uM ADP,Days,Primary Endpoint(%),30,Prasugrel,Clopidogrel,60,90,180,270,360,450,HR 0.77 P=0.0001,HR 0.80 P=0.0003,12.1 (781),9.9 (643),HR 0.81 (0.73-0.90) P=0.0004 NNT=46,ITT=13,608 LTFU=14(0.1%),TRITON TIMI-38 ACS (STEMI or UA NSTEMI) & Planned PCI Primary Endpoint : CV Death, MI, Stroke,N Engl J Med 2007; 357: 2001-15,ARD 0.6 HR 1.32 P =0.03 NNH =167,ARD 0.5 HR 1.52 P =0.01,ARD 0.2 P =0.23,ARD 0.3 P =0.002,ARD 0% P =0.74,TRITON TIMI-38 Bleeding Events Safety Cohort (n=13,457),ICH in Pts w Prior Stroke/ TIA (N=518) Clop 0(0) % Pras 6(2.3)% (P=0.02),N Engl J Med 2007; 357: 2001-15,Days,Endpoint(%),30,Prasugrel,Clopidogrel,60,90,180,270,360,450,12.1,9.9,TRITON TIMI 38 Balance of Efficacy and Safety,CV Death / MI / Stroke,2.4,1.8,TIMI Major NonCABG Bleeds,138 events HR 0.81 (0.73-0.90) P =0.0004 NNT =46,35 events HR 1.32 (1.03-1.68) P =0.03 NNH =167,N Engl J Med 2007; 357: 2001-15,Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit: risk balance,Safety Significant increase in serious bleeding (32%